An In Silico and In Vitro Approach to Develop Novel Iminopyridines as EmbB Arabinosyl Transferase Targets to Combat H37Rv Strains of Mycobacterium Tuberculosis

Abstract

Tuberculosis is a virulent infection caused by Mycobacterium tuberculosis and inclined as a major global health concern. Development of multidrug-resistance and extensively drug-resistance by strains, drug toxicity and co-infection with HIV are the significant reasons for limiting the success of existing therapies. Therefore, it is a challenge for medicinal chemists to develop safer, more effective, novel anti-TB drugs with new mechanisms of action which are able to eliminate existing drug related issues. The current study involved the design, synthesis, characterization, and in vitro anti-tubercular activity evaluation of new iminopyridine derivatives (Compounds S1-S10) Using the Schrödinger Maestro software, the compounds were subjected for molecular docking investigations against the EmbB protein of arabinosyl transferase enzyme (PDB ID: 6X0O) with which electron-withdrawing substituted derivatives engage favourably, according to docking studies. Hence all the designed compounds implied Lipinski's Rule of Five and exhibited acceptable pharmacokinetic characteristics, according to ADME prediction studies conducted using ADMET Lab 3.0 web server, the tailored compounds were synthesized and characterised by spectral methods.

Anti-tubercular activity was carried out by micro dilution broth method to measure minimum inhibitory concentration (MIC) of all compounds. Rifampicin, standard drug has MIC at 0.25 µg/mL. Compounds S1, S2 and S3 with electron withdrawing groups like nitro and halo groups showed the greatest efficacy among the produced derivatives at the 6.25, 42 and 50 µg/mL respectively. Compounds S5, S9 and S10 demonstrated poor activity event at 100 µg/mL and above, but Compound S6 shown moderate activity 90 µg/mL).